The present invention relates to transition metal-catalysed organic reactions in general, preferably reactions occurring via allyl-metal-intermediates, in particular microwave heated very rapid highly selective (chemo-, regio- and stereo-) allylic substitutions utilising molybdenum or palladium together with an auxiliary ligand as catalytic system.
Metal-catalysed asymmetric allylic substitution reactions have attracted considerable interest primarily due to their synthetic utility.1,2 The enantioselectivity in the reaction is determined either during complex formation or, with substrates yielding meso-allyl ligands, at the nucleophilic attack on either of the two diastereotopic allyl-carbon atoms of the allyl-metal intermediate. 1,2 The absolute configuration of the starting material is not recognised in the intermediate allyl-metal complex and high asymmetric induction can be achieved by the employment of chiral ligands. A plethora of C1- and C2-symmetric chiral ligands are available for this reaction class,3 and among these, multidentate ligands with phosphorus and/or nitrogen as coordinating elements have been most extensively used.2 Some of the recently developed nitrogen-based ligands deliver high enantioselectivities, but unsatisfactorily long reaction times are frequently required for full conversions.3 In drug discovery and screening procedures, such as when using the principles of combinatorial chemistry, these long reaction times may cause costly delays in the development of lead compounds and new drugs.
Flash-heating by microwaves for acceleration of organic reactions is well established,4 but it was only in the last few years that the power of the heating methodology was demonstrated in metal-catalysed coupling reactions, where the collapse of the catalytic system could be avoided by proper selection of conditions. The present applicant""s own International patent application No. WO 97/00794 relates to such microwave induced organic reactions. Thus, selective Heck,5 Suzuki,6 and Stille6 reactions, in solution or on solid phase, were accomplished in 1.5-12 min and in high yields with a variety of combinations of reactants.5a,e,f,6 
Other examples of microwave-stimulated reactions, apart from those disclosed in the literature references cited herein, are given in the following patent publications.
Thus, U.S. Pat. No. 4,279,722 discloses the enhancement of the conversion of liquid hydrocarbons derived from petroleum in a catalytic petroleum refinery process by exposing a mixture of hydrocarbons and catalyst to microwave in the frequency range of about 2.5xc3x97109 to 1012 Hz.
U.S. Pat. No. 5,215,634 discloses a process for selectively converting methane and a hydrating agent to C3 oxygenates. In particular, methane is reacted with water in the presence of a nickel metal powder catalyst using microwave irradiation to produce acetone and propanol.
U.S. Pat. No. 5,411,649 discloses selective production of ethane and ethylene in high yields by using particular catalysts and microwaves for controlled oxidation.
EP 0742189 A1 discloses production of an organo-nitrogen compound by irradiating a mixture of a catalyst, an organic compound and nitrogen with microwaves.
EP 0787526 A2 discloses the enhancement of catalytic reaction rates at low temperatures by utilising microwaves and other techniques, such as simulates boiling, ultrasonication, etc.
However, to the best of our knowledge, no reports have appeared on the impact of microwave irradiation on asymmetric transition metal catalysis in general, or on the reaction rate in such processes where allyl-metal complexes constitute a key intermediates in the catalytic cycle.
In view of the disadvantage of the known asymmetric allylic substitution reactions being so slow, the present inventors have developed a new method for performing asymmetric allylic substitution reactions. To the applicant""s best knowledge, no previous reports have appeared on the impact of microwave irradiation on asymmetric transition metal catalysis in general and in particular not on reactions where allyl-metal-complexes constitute the key intermediate in the catalytic cycle.
The present invention provides a method of performing a transition metal-catalysed allylic substitution reaction, comprising the steps of:
a) preparing a reaction mixture comprising; (i) an allylic substrate which includes the structural element Cxe2x95x90Cxe2x80x94Cxe2x80x94X, where X is a leaving group, (ii) a catalyst complex which includes a transition metal and one or more ligands, and (iii) a nucleophile; and
b) exposing said reaction mixture to microwave energy from a controllable microwave source.
The present invention also provides a method for preparing a compound library of products of a transition metal-catalysed allylic substitution reaction, comprising the steps of:
a) preparing a reaction mixture comprising (i) n different species of allylic substrates which include the structural element Cxe2x95x90Cxe2x80x94Cxe2x80x94X, where X is a leaving group, (ii) a catalyst complex which includes a transition metal and one or more ligands, and (iii) m different nucleophiles, wherein n is an integer in the range of 1-25 and m is an integer in the range of 1-10, with the proviso that the product nxc3x97m is at least 2, such as at least 3 or at least 4; and
b) exposing said reaction mixture to microwave energy from a controllable microwave source.
In the steps a(ii) in the methods according to the invention, the catalyst complex can in certain cases preferably be generated by microwave-stimulated reaction between a catalyst precursor (precatalyst) and the free ligand.
Thus, it is also possible within the present invention to provide compound mixtures especially valuable for screening purposes.
The methods according to the present invention are particularly interesting where an asymmetric catalyst is utilised in that an enantiometic/diastereomeric excess of the desired product thereby can be obtained.